5ARIs Raise Risk of Self-Harm, Depression

Study confirms small, but significant increases in the risks of these mental health problems among men taking the medication.

In keeping with postmarketing experience, a new study finds a slight increase in the risks of self-harm and depression among users of 5 alpha-reductase inhibitors (5ARIs).

The class of medications treats benign prostatic hyperplasia (BPH) and related lower urinary symptoms (LUTS) along with androgenic alopecia, and includes finasteride and dutasteride.

Previous studies and anecdotal experience purported suicidal ideation and depression with the medication. To formally evaluate the claims, Blayne Welk, MD, MSc, of St Joseph's Health Care in London, Ontario, and colleagues used several health resource and prescription databases from Ontario, Canada. They compared the risks of suicide, self-harm, and depression in 93,197 men older than 66 years who started a 5ARI during 2003 to 2013 with a similar number of men not taking the drugs. The cohorts were matched for 44 covariates that covered medical comorbidities, medication usage, and health care system utilization, to reduce the risks of confounding. Men with depression in the previous 5 years were excluded.

No greater risk of suicide was found for 5ARI users, according to results published in JAMA Internal Medicine. But the risks of self-harm and new-onset depression increased by 88% and 94%, respectively, during the first 18 months of medication use. After that period, the risk of self-harm subsided, whereas the risk of depression continued abated at 22%. Self-harm was considered a suicide attempt resulting in an emergency department visit or a related psychiatric hospital admission.

In the study's background information, the investigators noted some potential mechanisms by which 5ARIs might influence mental health. First, inhibiting 5 alpha-reductase enzymes might suppress the production of some neuroactive steroids. Second, the medications affect the conversion of testosterone to dihydrotestosterone, which plays a role in the neuroendocrine stress response. Third, reduced levels of the neurosteroid allopregnanolone produced by 5 alpha-reductase are found in men with depression. Last, depressed patients tend to have less type I 5 alpha-reductase in the prefrontal cortex.

In absolute terms, few patients would be affected by such side effects. Thoughts or attempts at self-injury would occur in 17 patients and depression in 237 patients per 100,000 per year. Results did not vary by type of 5ARI.

“The absolute increased risk of these 2 outcomes was low, and the potential benefits of 5ARIs in this population likely outweigh these risks for most patients,” Dr Welk and colleagues stated. LUTS itself may lead to worse quality of life and perhaps depression, they noted. Yet, the risks are relevant for some men. “In patients presenting with thoughts or evidence of self-harm, or with a new diagnosis of depression, the continued use of this medication should be reevaluated,” they added.

In an accompanying editorial, Stephen Thielke, MD, MS, of the Geriatric Research, Education, and Clinical Center, Puget Sound VA Medical Center, Seattle, discuss whether and how a clinician should counsel patients. Some options include prescribing other drugs for LUTS that are not know to increase depression risk; giving clear warning to all patients about the possible risks; monitoring carefully for depression during 5ARI use; and warning those who have had prior depression about the risks.